JP2023515614A - Method for producing methylene blue - Google Patents

Abstract

The present disclosure provides methods for making 3,7-bis-(dimethylamino)-phenothiazin-5-ium chlorides of formula (I). TIFF2023515614000014.tif3652 The method comprises preparing a wet crude crude of 3,7-dibromophenothiazin-5-ium bromide (III) from phenothiazine (II) together with a promoter, a catalyst and a brominating agent in the presence of an organic solvent. preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) from 3,7-dibromophenothiazin-5-ium bromide; and 3,7-bis-(dimethylamino)- Preparation of 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride from phenothiazin-5-ium bromide followed by 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I ) and removing metal components from 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) by a metal scavenger. The method eliminates the additional step of an ion exchange column in the reaction and provides a product purity of 99-99.5%.

Description

(Field of Invention)
The present invention relates to a method (or process) for making (or preparing) 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I). More specifically, the present invention provides a method for producing (or preparing) 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) of formula (I) shown below in high purity ( or process).

(Background of the invention)
3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (also known as methylthioninium chloride, methylene blue, MTC) is a phenothiazine dye for hair, leather and cellulose fibres. , redox indicators (or redox indicators), photosensitizers (or photosensitizers) for singlet oxygen generation, antioxidants, antiseptic stains for fixed living tissue, renal function tests It is well known as a diagnostic agent for Methythioninium Chloride (MTC) (also known as methylene blue) is a tricyclic organic compound with a low molecular weight (319.86) and water solubility.

Methylene blue has many uses in various fields, such as those in biology and chemistry. Methylene blue appears as a solid, odorless, dark green powder at room temperature, but produces a blue solution when dissolved in water. Methylene blue should not be confused with methyl blue (another histological stain), new methylene blue, methyl violet (often used as a pH indicator).

Methylene blue is an ingredient in frequently prescribed urinary analgesics/anti-infectives/antispasmodics, and is also used in "Prosed" (also called phenyl salicylate, benzoic acid, hyoscyamine sulfate, methenamine (also known as hexamethylene tetramine, which should not be confused with "methanamine").

Methylene blue is also well known as a phenothiazine dye and redox indicator, and has also been used as a redox mediator, as an intercalator in nanoporous materials, and as an optical probe in biophysical systems. See, eg, Color Index (Vol.4, 3rd edition, 1971), Lillie et al., 1979, and references cited therein. Methylene blue is currently used to treat methemoglobinemia, a condition that occurs when the blood can no longer carry oxygen where it is needed in the body.

Methylene blue is also used as a medical dye (e.g. to stain specific parts of the body before or during surgery), a diagnostic agent (e.g. as an indicator dye for detecting certain compounds present in urine), It is used as a mild urinary antiseptic, mucosal surface irritant, treatment and prevention of kidney stones, diagnosis and treatment of melanoma.

Methylene blue was first described in a German patent of 1877 (Badische Anilin- und Soda-Fabrik, 1877). Here, nitrosylation (or nitrosylation) of dimethylaniline, followed by reduction to form N,N-dimethyl-1,4-diaminobenzene, followed by hydrogen sulfide (H ₂ S) and iron(III) chloride ( have synthesized methylene blue by oxidative coupling in the presence of FeCl ₃ ). Therefore, this patent uses more metal ions, thereby increasing the metal component (or metal content or metal content) in the product.

(Prior art and its shortcomings)
Canadian patent application no. ), including methods for synthesizing and purifying ). nitrosyl reduction thiosulfonic acid formation; oxidative coupling; Cr(VI) reduction; isolation and purification of zwitterionic intermediates; dimethyldithiocarbamate treatment; carbonate treatment; ethylenediaminetetraacetic acid treatment (EDTAT); organic extraction and recrystallization. This invention also provides the compounds obtained, compositions containing them (e.g. tablets, capsules), methods of inactivating pathogens, methods of medical treatment and diagnosis, etc. (e.g. tauopathy, Alzheimer's disease (AD)). , skin cancer, melanoma, viral, bacterial or protozoan diseases).
The present invention now provides, in the final formula (I), an improved method (or process) for the production (or preparation) of high-purity methylene blue with reduced metal components (or metal content or metal content) )I will provide a.
The above patent application fails (or does not disclose) to provide an improved method of high purity. Furthermore, it also fails (or does not disclose) to reduce the metal component (or metal content or metal content) in 3,7-diamino-phenothiazin-5-ium compounds.

European Patent Application No. EP3375777A1 describes a method (or process) for making (or preparing) 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide or chloride; )-phenothiazin-5-ium bromide to 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride; and 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride A pharmaceutically acceptable 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (methylthioninium chloride, methylene blue , MTC).

However, the above patent application describes a method (or process) for producing (or preparing) 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide or chloride using phenothiazine in the presence of a metal catalyst. is disclosed. In the above patent application, an ion exchange column step (or step) is added for purification. This increases the number of processing steps, increasing the cost and complexity of the process.
In contrast, the present invention provides an improved method (or process) for the production (or preparation) of methylene blue. The method eliminates the additional step (or steps) of the ion exchange column. This reduces the cost of the process.
Therefore, the above applications fail to provide (or do not disclose) an improved method (or process) for the production (or preparation) of methylene blue in high purity.

US Patent Application No. US20090291943A1 relates to a method (or process) for making (or preparing) diaminophenothiazinium-based compounds. The method includes a process (or steps) for purifying the derivative.
In contrast, the present invention provides an improved method (or process) for the production (or preparation) of methylene blue in high purity and yield, wherein the metal component (or metal-containing volume or metal content).
Also, the above patent application fails (or does not disclose) to reduce the metal component (or metal content or metal content) present in methylene blue.
In contrast, the present invention provides a reduced metal component (or metal content or metal content) in methylene blue.

US Patent Application No. US20200010438A1 relates to a method for making (or preparing) 3,7-bis(dimethylamino)phenothiazin-5-ylium iodide (or iodide). The method uses phenothiazine as a starting material. The method includes the following steps (a) and (b).
(a) treating the phenothiazine with diiodine (or diiodine); and (b) treating the reaction medium obtained directly from step (a) above with dimethylamine. However, in the above patent application different reagents are used. different processes are disclosed. Also, the above patent application fails (or does not disclose) to reduce the metal component (or metal content or metal content) in methylene blue.
Therefore, the above application fails (or does not disclose) an improved method (or process) for the production (or preparation) of methylene blue in high purity.

Accordingly, there is an unmet need for improved methods (or processes) for producing (or preparing) methylene blue in high yield and purity.

(Disadvantages of prior art)
As listed below, conventional methylene blue manufacturing methods (or processes) have a number of disadvantages (or shortcomings).
1. Conventional methods (or processes) cannot provide improved methods (or processes) for producing (or preparing) methylene blue with high purity.
2. In most of the conventional methods (or processes), the percentage of metal contained in methylene blue is high.
3. Most conventional methods (or processes) use the additional step (or steps) of ion exchange columns to produce (or prepare) methylene blue.
4. In most of the existing prior art methods (or processes), methylene blue contains a high percentage of impurities, which reduces the efficiency and increases the cost of the product.

(Purpose of Invention)
The main object of the present invention is to provide a method (or process) for producing (or preparing) methylene blue with a high percent purity.
Another object of the present invention is to provide a method (or process) for the production (or preparation) of methylene blue that achieves pharmaceutical grade.
Yet another object of the present invention is to provide a method (or process) for the production (or preparation) of methylene blue with a small percentage (%) of metal component (or metal content or metal content) to provide.
Yet another object of the present invention is to provide a method (or process) for the production (or preparation) of methylene blue that eliminates the additional step (or step) of an ion exchange column in the reaction.
Yet another object of the present invention is a method for producing (or preparing) methylene blue that reduces the percentage of organic and inorganic impurities, thereby increasing the efficiency of the process and reducing the cost of the process. (or process).

(Gist of Invention)
Method (or process) for making (or preparing) 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride (I)
The process includes the following processes (or steps).

(a) preparing 3,7-dibromophenothiazin-5-ium bromide (III) from phenothiazine (II) with a promoter (or promoter), catalyst and brominating agent in the presence of an organic solvent;
(b) preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) from 3,7-dibromophenothiazin-5-ium bromide;
(c) preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride from 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide;
(d) purifying the product to remove the metal component (or metal content or metal content) from 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) by a metal scavenger;

(Detailed description of the invention)
The present invention provides a method (or process) for producing (or preparing) methylene blue with high purity. The methylene blue method eliminates the additional step (or step) of an ion exchange column in the reaction. The present invention reduces the percentage of organic and inorganic impurities, thereby increasing the efficiency and lowering the cost of the process. The methylene blue process consists of phenothiazine (II), which reacts with the promoter (or accelerator), p-toluenesulfonic acid (PTSA).

The catalyst is selected from, but not limited to, metal catalysts and boron trifluoride-acetic acid complexes. Here, the boron trifluoride-acetic acid complex contains water. For example, _boron trifluoride hydrate ( _BF3.H2O ). Complexes of boron trifluoride-acetic acid with alcohols, ethers, carboxylic acid esters or nitriles include boron fluoride-ethyl acetate complex (C ₄ H ₈ O ₂ BF ₃ ), boron fluoride-methylbenzoate complex, fluorine Boron fluoride-methanol complex (BF ₃ —CH ₃ OH), boron fluoride-ethanol complex (BF.C ₂ H ₅ OH), boron fluoride-glycol complex (BF ₃ —(CHOH) ₂ ), boron trifluoride - etherate ( _C4H10BF3O ), _boron trifluoride-methyl _{amyl ether complex} ( _{BF3.C6H14O )} , boron trifluoride-anisole complex _{( BF3.C6H5OCH3 )} , boron trifluoride-tetrahydrofuran complex (BF ₃ —C ₄ H ₈ O), boron trifluoride-dioxane complex (BF ₃ —C ₄ H ₈ O ₂ ), boron trifluoride-acetonitrile complex (BF ₃ —CHCN ), boron trifluoride-benzonitrile complex (BF _{3.CH 5} CN), boron trifluoride complex with o,m,p-toluonitrile, but not limited thereto .
Said metal catalysts are selected from Group VIII metals of the periodic table (eg, iron, cobalt, nickel), but are not limited thereto.
In other embodiments, the metal catalyst is selected from, but not limited to, Group IB metals of the periodic table (eg, copper and/or silver).
In other embodiments, the metal catalyst is selected from Groups IIIB and IIIA metals of the Periodic Table.

The compound for bromination (or bromination compound or brominating agent) is selected from, but not limited to, 1,3-dibromo-5,5-dimethylhydantoin and bromine. 3,7-Bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) is prepared by adding Diemethylamine (DMA) and an organic solvent. The organic solvent is selected from polar and non-polar solvents, ethyl acetate, methanol, isopropyl alcohol acetate, aqueous hydrochloric acid (or aqueous hydrochloric acid), hydrochloric acid (HCl), chloroform and polar protic and aprotic solvents, Examples include, but are not limited to, dichloromethane, methyl acetate, butyl acetate and mixtures thereof.

A metal scavenger removes metal impurities from the product.
Metal scavengers include polymeric resin materials, silica-based micropores, silicycle triamine, Quadrasil MP, Aliquat 336, silica gel functionalized with AMPA (≥99%), bipyridine (polymer bound) (100- 200 mesh), silica gel functionalized with cysteine, silica gel functionalized with 3-(diethylenetriamino)propyl, DL-dithiothreitol (polymer bound), silica gel functionalized with DMT, silica gel functionalized with DOTA. silica gel, ethylenediaminetriacetic acid acetamide (polymer-bound), silica gel functionalized with 3-(ethylenediamino)propyl, 2-mercaptoethylamine (polymer-bound), silica gel functionalized with 3-mercaptopropyl, on silica gel of silica gel (≧99%) functionalized with N-propyldiethanolamine or QuadraPure® AEA, QuadraPure® AMPA (macroporous), QuadraPure® BDZ, QuadraPure® ® BZA, QuadraPure ® EDA, QuadraPure ® IDA (macroporous), QuadraPure ® MPA, QuadraPure ® TU (macroporous), 3-(1-thioureido) ) propyl, triamine tetraacetate (silica-supported), silica gel functionalized with triamine tetraacetate sodium salt, silica gel functionalized with triamine tetraacetate, triamine tetraacetate sodium salt (silica-supported), N, N , N′-trimethylethylenediamine (polymer bound), Biotage® MP-TMT or ISOLUTE® Si-TMT or ISOLUTE® Si-thiol or ISOLUTE® SCX-2 or ISOLUTE® ( ® Si-Trisamine or Phosphon SPM32, but not limited thereto. The metal scavengers described above reduce the metal component (or metal content or metal content) in methylene blue to within the range <1 ppm to 10 ppm , more preferably <1 ppm to 3 ppm.

In a preferred embodiment, the improved method (or process) of the present invention for producing (or preparing) methylene blue comprises the following steps (or steps).

step (a)
Preparation of 3,7-dibromophenothiazin-5-ium bromide (i.e. formula (III)) from phenothiazine (II) As shown in Scheme 1, p-toluenesulfonic acid (PTSA), a catalyst and A round-bottomed flask is charged with phenothiazine (II) under nitrogen gas atmosphere along with the brominating agent.
Here, the catalyst is selected from, but not limited to, metal catalysts and boron trifluoride-acetic acid complexes.
The compound for bromination (or bromination compound or brominating agent) is selected from, but not limited to, 1,3-dibromo-5,5-dimethylhydantoin and bromine.
Organic solvents are selected from, but not limited to, ethyl acetate, methanol, acetic acid and chloroform.

Stir the reaction at a temperature of -20°C to -30°C to prepare 3,7-dibromophenothiazin-5-ium bromide (III).

step (b)
Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) The product (3,7-dibromophenothiazine-5- To the above-titled product (3 ,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV)).

step (c)
Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) 3,7-bis-(dimethylamino)-phenothiazine obtained in step (b) (or step (b)) above -5-ium bromide (IV) is dissolved in an organic solvent followed by the addition of 0.5M HCl solution. The reaction(s) was refluxed at a temperature of 40° C.-80° C. for 2-3 hours. A metal scavenger is added to the reaction mixture at a temperature of 50°C and left at a temperature of 15°C to 20°C. The product is washed with a cold organic solvent and dried to give the above-titled product (3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I)).

The present invention provides a method (or process) for manufacturing (or preparing) methylene blue. The method eliminates the additional step of ion exchange columns in the reaction and provides purities of 99-99.5%.

Examples Example 1 (A)
Phenothiazine (II) (100 g) was charged to a round bottom flask under nitrogen gas atmosphere. Subsequently, ethyl acetate was added at room temperature. To this mixture was added boron trifluoride-acetic acid complex (19 g). The temperature was lowered to -20°C. PTSA.H ₂ O (p-toluenesulfonic acid) (6 gm) was added to this mixture. Bromine solution (64 ml) was then added dropwise. The reaction was maintained at -20°C to -25°C for 2 hours. Methanol was added to this mixture. A 40% aqueous DMA (450 g) solution was then added dropwise. The reaction mass was washed with ethyl acetate (200 ml) solution to give 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) as crude.

Example 1 (B)
Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (137 g) obtained as described above was Place in another round-bottomed flask under nitrogen gas atmosphere. Methanol (520 ml) was added to the mixture. The reaction was maintained at 50-55° C. with constant stirring for 1 hour. The product thus obtained was filtered, washed with methanol and dried. To this mass was added a mixture of methanol and 0.5 M HCl solution and the reaction was heated at 50-55° C. for 1 hour with constant stirring. The reaction was cooled, followed by filtration and washing with methanol to give the title product above.

Example 2 (A)
A round bottom flask was charged with phenothiazine (II) (7.5 kg) under nitrogen gas atmosphere. Subsequently, ethyl acetate was added at room temperature. Aluminum chloride (22.5 gm) was added to this mixture. The temperature was lowered to −25° C. followed by dropwise addition of bromine solution (15 kg). The reaction was maintained at -20°C to -25°C for 2 hours. Methanol was added to this mixture. Subsequently, a 40% aqueous DMA solution was added dropwise. The reaction mass was washed with ethyl acetate (200 ml) solution to give 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) as crude.

Example 2 (B)
Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide obtained as described above (6.35 g ) is placed in another round-bottomed flask under a nitrogen gas atmosphere. Methanol (3.8 l) was added to the mixture. The reaction was maintained at 50-55° C. with constant stirring for 1 hour. The product thus obtained was filtered, washed with methanol and dried. To this mass was added a mixture of methanol and 0.5M HCl solution. The reaction(s) was heated at 50-55° C. for 1 hour with constant stirring. Cooling of the reaction(s) followed by filtration and washing with methanol gave the title product above.

Example 3 (A)
Purification of methylene blue Methylene blue (75 g) obtained by the above method was charged into a round bottom flask under nitrogen gas atmosphere. Methanol (137 ml) was then added at room temperature. To this mixture was added 0.5M HCl solution (548ml). The reaction was heated at 50-55° C. with constant stirring. To this mixture was added silicycle triamine (2.0 gm). The reaction was maintained at 55-60° C. with constant stirring for 1 hour. The product thus obtained was filtered and washed with methanol and dried to obtain pure product (I).

Example 3 (B)
Methylene blue (75 g) obtained by the method described above was charged to a round-bottomed flask under a nitrogen gas atmosphere. Subsequently, 0.2M HCl solution (1100 ml) was added at room temperature. The reaction was heated at 50-55° C. with constant stirring. Quadrasil MP (2.0 g) was added to this mixture. The reaction was maintained at 55-60° C. with constant stirring for 1 hour. The product thus obtained was filtered and washed with methanol and dried to give pure product (I).

Example 3 (C)
Methylene blue (50 g) obtained by the above method is injected into a round-bottomed flask under nitrogen gas atmosphere, followed by addition of 0.2 M HCl solution (733 ml) at room temperature. Heat the reaction(s) at 50-55° C. with constant stirring. Aliquat 336 (0.25 g) was added to this mixture. The reaction was maintained at 55-60° C. with constant stirring for 1 hour. The product thus obtained was filtered and washed with methanol and dried to obtain pure product (I).

Exemplification of the present invention has been performed by HPLC. A purity of 98-99.7% is obtained here for methylene blue. Metal components are detected by an ICP-MS (Inductively Coupled Plasma Mass Spectrometry) device.

Claims (9)

A process for producing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride (I), the process comprising the following steps (a) to (d):

(a) preparing a wet crude of 3,7-dibromophenothiazin-5-ium bromide (III) from phenothiazine (II) with a promoter, a catalyst and a brominating agent in the presence of an organic solvent;
(b) preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) from 3,7-dibromophenothiazin-5-ium bromide;
(c) preparing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride from 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide;
(d) Purification of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) and removal of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) by a metal scavenger ) removing metal components from
A method, including A method for producing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride according to claim 1, wherein said catalyst is a metal catalyst and a boron trifluoride-acetic acid complex. The method for producing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride according to claim 1, wherein said promoter is p-toluenesulfonic acid (PTSA). A process for preparing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride according to claim 1, using dimethylamine (DMA) as a reagent. 3,7-bis(dimethylamino)-phenothiazine-5 according to claim 1, wherein said brominating agent is selected from, but not limited to, bromine and 1,3-dibromo-5,5-dimethylhydantoin. - a method for producing ium chloride. 3. Claim 3, wherein the organic solvent is selected from, but not limited to, ethyl acetate, methanol, isopropyl alcohol acetate, hydrochloric acid (HCl), chloroform, dichloromethane, methyl acetate, butyl acetate and mixtures thereof. ,7-bis(dimethylamino)-phenothiazin-5-ium chloride. The metal scavengers are polymeric resin materials, silica-based micropores, silicyl triamines, Quadrasil MP, Aliquat 336, AMPA functionalized silica gel (≧99%), bipyridine (polymer bound), cysteine functionalized. 3-(diethylenetriamino)propyl-functionalized silica gel, DL-dithiothreitol (polymer-bound), DMT-functionalized silica gel, DOTA-functionalized silica gel, ethylenediaminetriacetic acid acetamide (polymer 3-(ethylenediamino)propyl-functionalized silica gel, 2-mercaptoethylamine (polymer-bound), 3-mercaptopropyl-functionalized silica gel, mixture of metal scavengers on silica gel, N- Silica gel (≧99%) functionalized with propyldiethanolamine or QuadraPure® AEA, QuadraPure® AMPA (macroporous), QuadraPure® BDZ, QuadraPure® BZA, QuadraPure® Trademarks) EDA, QuadraPure® IDA (macroporous), QuadraPure® MPA, QuadraPure® TU (macroporous), 3-(1-thioureido)propyl, triamine tetraacetate (on silica) type), silica gel functionalized with triamine tetraacetic acid sodium salt, silica gel functionalized with triamine tetraacetic acid, triamine tetraacetic acid sodium salt (silica-supported), N,N,N'-trimethylethylenediamine (polymer-bound type), Biotage® MP-TMT, ISOLUTE® Si-TMT, ISOLUTE® Si-thiol, ISOLUTE® SCX-2, ISOLUTE® Si-Trisamine, Phosphon S 3,7-bis(dimethylamino)- according to claim 1, selected from, but not limited to, SPM32 in the range <1 ppm to 10 ppm, more preferably <1 ppm to 3 ppm Process for producing phenothiazin-5-ium chloride. Process for preparing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride according to claim 1, wherein the proportion of organic impurities is in the range of 0.1-0.35%. The process for producing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride according to claim 1, wherein the purity percentage is in the range of 99-99.5%.